Germ cell tumor classification

Germ cell tumors can be classified based on their histologic features into:

Germ cell tumors

Germinomatous/Undifferentiated/Immature

Nongerminomatous/Differentiated/Embryonal

Dysgerminoma(Ovary)

Seminoma(Testis)

Embryonal carcinoma

embryonic tissue

Extraembryonic tissue

Teratoma

Yolk sac tumor

Choriocarcinoma

Germ cell tumors

Germinomatous/Undifferentiated/Immature

Nongerminomatous/Differentiated/Embryonal

Dysgerminoma(Ovary)

Seminoma(Testis)

Embryonal carcinoma

embryonic tissue

Extraembryonic tissue

Teratoma

Yolk sac tumor

Choriocarcinoma

Germ cell tumors classification is based on the histologic features and whether they are differentiated or not into:

• Germinomatous tumors: (non-differentiated): Gonadal and Extra-gonadal
  • Germinoma ( Gonadal: dysgerminoma and seminoma), (Extra-gonadal: mediastinum, or pineal region)
  • Dysgerminoma (Ovary)
  • Seminoma (testes)
• Nongerminomatous tumors: all other germ-cell tumors, pure and mixed
  • Embryonal carcinoma
  • Endodermal sinus tumor, also known as yolk sac tumor (EST, YST)
  • Choriocarcinoma
  • Teratoma including mature teratoma, dermoid cyst, immature teratoma, teratoma with malignant transformation
  • Polyembryoma
  • Gonadoblastoma
• Mixed germ cell tumors:

Germ cell tumors can also be classified based on their location into:

• Gonadal (ovary and testes)
• Extra-gonadal (MC:mediastinum, retroperitoneal. Less common: Pineal gland, sacrococcigeal)

• Ovarian germ cell tumors (OGCTs ): The histologic types that arise from the ovary are similar to those arising from the testes of men
  • Embryo-like neoplasms
    • Teratomas and their subtypes
    • Dysgerminomas: The female version of the male seminoma (comprised of immature germ cells)
  • Extraembryonic fetal-derived (placenta-like) cell populations
    • Yolk sac/primitive placenta forms (epithelial neoplasms differentiate into yolk sac tumors)
  • Rare OGCTs
    • Pure embryonal carcinomas
    • Nongestational choriocarcinomas
    • Pure polyembryoma.
  • Mixed germ cell tumors (teratoma with yolk sac, dysgerminoma, and/or embryonal carcinoma)
• Extragonadal germ cell tumors (GCTs): no evidence of a primary tumor in the testes or ovaries
  • Typically arise in midline locations,
  • Specific sites vary with age
  • The most common sites in order of frequency
  • In adults:
    • Anterior mediastinum
      • Mature teratomas
      • Immature teratoma
      • Mediastinal seminoma
      • Mediastinal non-seminomatous GCT:
        • Yolk sac tumor (most common, pure or mixed)
        • Choriocarcinoma (less common)
        • Embryonal carcinoma (infrequent)
        • Mixed GCTs (a mixture of teratoma, seminoma, and other cell types)
    • Retroperitoneum
      • Retroperitoneal seminoma
      • Retroperitoneal non-seminomatous GCTs (Embryonal carcinoma is common)
      • Retroperitoneal teratomas (rare)
    • Pineal and suprasellar regions
  • In infants and young children:
    • Sacrococcygeal
    • Intracranial GCTs

Types	Subtypes	Signs and Symptoms	Histopathology	Lab finding	Prognosis
Germinomatous /Undifferentiated	Seminoma (Testis)	Painless testicular mass with discomfort Back pain Abdominal discomfort Abdominal mass.	Gross: pale gray to yellow nodules that are uniform or slightly lobulated and often bulge from the cut surface	Complete blood count and blood chemistry tests. Abnormal serum tumor marker levels (LDH, HCG). CT: Metastases to the para-aortic, inguinal, or iliac lymph nodes. Visceral metastasis may also be seen. Pelvic MRI: may be diagnostic. multinodular tumors of uniform signal intensity Hypo- to isointense on T2-weighted images and inhomogenous enhancement on contrast enhanced T1-weighted images. Other diagnostic studies for seminoma include biopsy, FDG-PET scan, and bone scan.	Prognosis of seminoma is good for all stages with greater than 90% cure rate. The International Germ Cell Cancer Consensus Group divides seminoma into two prognosis groups: good and intermediate. Common complications of seminoma include recurrence, lymph node metastasis, distant metastasis, and secondary malignancies.
Dysgerminoma (Ovary)	Depend on the type of the tumor and its potential to produce hormonalmaterials Abdominal pain or distention Menstrual irregularities Symptoms of virilization Rapidly growing abdominal/pelvic mass Acute abdominal pain from complications such as: Necrosis Capsular distention Rupture or torsion and or simply they can be asymptomatic.	The majority of ovarian germ celltumors have a solid and cystic appearance with areas of hemorrhageand necrosis A uniform “fried egg” appearance (dysgerminoma)	Beta-hCG to rule out pregnancy in women with abdominopelvic symptoms Cultures for gonorrhea and chlamydia and a wet mount in reproductive and sexually active women to role out and treat before surgery if positive. Lactate dehydrogenase (LDH), alpha-fetoprotein (AFP), beta-human chorionic gonadotropin (beta-hCG) levels. If any levels are elevated, they may assist in diagnosis and/ or follow-up of women diagnosed with malignant ovarian GCTs. Inhibin A and B Cancer antigen 125 (CA-125) - For epithelial tumors Ultrasound: Dysgerminoma often appears as a hypoechoic mass	Chemotherapy: except those with stage 1a, stage 1a, 1b dysgerminoma Radiotherapy: ** Dysgerminoma is radiosensitive. ** Radiotherapy is not anymore the first option of treatment for dysgerminoma considering its association with ovarian failuredevelopment. Surgery: for diagnostic grading and therapy depending on if the patient prefers to preserve the ovary or not.
Germinomatous/ Differentiated	Embryonic
Teratoma	Chest pain Cough Shortness of breath Abdominal pain Lump, Abdominal(ovarian teratoma) Abnormal bleeding from the vagina Fatigue, weight loss Limited ability to tolerate exercise	Teratomas belong to a class of tumors known as nonseminomatous germ cell tumor (NSGCT). All tumors of this class are the result of abnormal development of pluripotent cells: germ cells and embryonal cells. Teratomas of embryonal origin are congenital; teratomas of germ cell origin may or may not be congenital (this is not known). Embryonal teratomas most commonly occur in the sacrococcygeal region: sacrococcygeal teratoma is the single most common tumor found in newborn babies.	AFP MSAFP CT scans are often used to diagnose teratoma.	For malignant teratomas, usually, surgery is followed by chemotherapy. Teratomas that are in surgically inaccessible locations, or are very complex, or are likely to be malignant (due to late discovery and/or treatment) sometimes are treated first with chemotherapy.
Extraembryonic
Choriocarcinoma(Gestational Trophoblastic Neoplasia)	Early Symptoms: Vaginal bleeding Nausea and vomiting Passing of tissue resembling a “bunch of grapes” from the vagina Absent fetal movement during pregnancy Abdominal distension Rare Symptoms: Headache Edema of the hands and feet Abdominal or pelvic pain Vaginal discharge Overactive thyroid gland (hyperthyroidism) that causes: Tachycardia Sweating Shaking Heat intolerance Fever Late Symptoms Hemoptysis Dry cough Chest pain Trouble breathing Headache Dizziness Jaundice Paralysis Seizure Dysarthria and dysphasia Vision problems Lump in the vagina	Gross pathological: Bulky, destructive mass with hemorrhage and necrosis Can be associated with deep myometrial invasion Microscopic histopathological: Columns and sheets of trophoblastic tissue invading uterine muscle and blood vessels Syncytiotrophoblasts (large eosinophilic smudgy multinucleated cells with large hyperchromatic nuclei) are intermixed with cytotrophoblasts (polygonal cells with distinct borders, and single irregular nuclei)	Human chorionic gonadotropin (HCG or b-HCG) is the most common tumor marker test used to diagnose GTD Human placental lactogen (hPL) is a tumor marker that may be used to follow women with placental site trophoblastic tumors Elevated hPL levels are found in women with some types of GTD Complete blood count can check for anemia from long-term (chronic) vaginal bleeding	Poor prognosis of gestational trophoblastic neoplasia (GTN) can be determined by the following factors: Age over 35 years (P = 0.025) Interval since the last pregnancy of over 2 years (P = 0.014) Deep myometrial invasion (P = 0.006) Stage III or IV (P < 0.0005) Maximum βhCG level > 1000 mIU/ml (P = 0.034) Extensive coagulative necrosis (P = 0.024) High mitotic rate (P = 0.005) Presence of cells with clear cytoplasm (P < 0.0005)
Yolk sac tumor (Endodermal sinus tumor)	Symptoms: Abdominal distention Acute/sub acute abdominal pain Signs: Abdomen: Abdominal distention Abdominal tenderness Pelvis: Adnexal mass	On gross pathology: Encaptulated, firm, smooth, round, globular, solid gray-white with a gelatinous, myxoid, or mucoid appearance, necrosis, cystic changes, and hemorrhage are characteristic findings of endodermal sinus tumor. On microscopic histopathological analysis: Schiller-Duval bodies (invaginated papillary structures with central vessel) is a characteristic finding of endodermal sinus tumor. The tumors are composed of irregular space lined by flattened to cuboidal cells and recticular stroma	An elevated concentration of serum alpha feto-protein is diagnostic of endodermal sinus tumor. AFP is very important for diagnosis, disease monitoring and early metastasis Endodermal sinus tumor may also be diagnosed using biopsy and measurement of GATA-4, a transcription factor	Endodermal sinus tumor has a poor prognosis in adult. Endodermal sinus tumor has a favorable prognosis in children. Endodermal sinus tumor is the most common malignant germ cell tumor in children. If left untreated, endodermal sinus tumor quickly metastasizes in other parts of the body such as the brain. Endodermal sinus tumor can be found in the ovaries or testicles including the chest, abdomen, and the brain. Ovarian germ cell tumor (endodermal sinus tumor) is surgically staged using the FIGO cancer staging system: